Prediction of sensitivity to fluoropyrimidines by metabolic and target enzyme activities in gastric cancer

Terashima, Masanori; Fujiwara, Hisashi; Takagane, Akinori; Abe, Kaoru; Irinoda, Takashi; Nakaya, Tsutomu; Yonezawa, Hitoshi; Oyama, Kenichi; Saito, Kazuyoshi; Kanzaki, Norio; Ohtani, S.; Nemoto, Tsuyoshi; Hoshino, Yutaka; Kogure, Michihiko; Gotoh, Mitsukazu

doi:10.1007/s10120-003-0221-z

Cited by 33 publications

(24 citation statements)

References 39 publications

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“…As a result, we could not confirm that the pharmacokinetics of S-1 differed between the high- and low-dose groups, and it might have been affected not only by the initial dose but by other factors, such as catabolic enzyme and renal function. Dihydropyrimidine dehydrogenase and thymidylate synthase are the rate-limiting enzymes that catabolize 5-fluorouracil, and these enzymes were reported to correlate with the effect of S-1 [22,23,24]; however, these enzyme levels were not examined in the current study. Renal function may also affect the deviation of the plasma concentration of S-1.…”

Section: Discussioncontrasting

confidence: 38%

Unexpected Side Effects of a High S-1 Dose: Subanalysis of a Phase III Trial Comparing Gemcitabine, S-1 and Combinatorial Treatments for Advanced Pancreatic Cancer

Kobayashi

Ueno²,

Irie³

et al. 2016

Oncology

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Objective: In this subanalysis of a phase III trial using three categorized doses of S-1, the influence of the actual doses on safety and efficacy was evaluated. Methods: We compared the efficacy and safety of the S-1 or gemcitabine plus S-1 combination (GS) arm between the top 10% group and the bottom 10% group according to the initial doses of S-1: ≥77.6 versus ≤65.9 mg/m²/day (n = 28 vs. 28) in the S-1 arm, and ≥65.1 versus ≤53.8 mg/m²/day (n = 27 vs. 28) in the GS arm. Results: Overall and progression-free survival were not significantly different between these two groups: hazard ratios of 0.818 and 0.761 with p values of 0.498 and 0.330 in the S-1 arm, and hazard ratios of 0.836 and 0.759 with p values of 0.557 and 0.323 in the GS arm, respectively. Incidences of grade 3-4 hematological toxicities were significantly higher in the top 10% group than in the bottom 10% group: 42.9 versus 14.3 and 85.2 versus 57.1%, with p values of 0.037 and 0.037 in the S-1 and the GS combination arm, respectively. Conclusions: Higher actual doses of S-1 were associated with a higher incidence of hematological toxicity even in the same dose setting.

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Section: Discussioncontrasting

confidence: 38%

Unexpected Side Effects of a High S-1 Dose: Subanalysis of a Phase III Trial Comparing Gemcitabine, S-1 and Combinatorial Treatments for Advanced Pancreatic Cancer

Kobayashi

Ueno²,

Irie³

et al. 2016

Oncology

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“…Due to this function, TP expression has been studied as a possible predictive marker for 5-FU -based chemotherapeutic regimens in various cancers, but the data have been inconsistent (26,27). In gastric cancer, no correlation between TP expression and response was found in the adjuvant setting (11). Others have reported correlation of high TP levels with response and high expression levels have been found to predict a more favorable prognosis after a postoperative chemotherapy (10,28,29).…”

Section: Discussionmentioning

confidence: 99%

Combined GADD45A and Thymidine Phosphorylase Expression Levels Predict Response and Survival of Neoadjuvant-Treated Gastric Cancer Patients

Napieralski¹,

Ott²,

Kremer³

et al. 2005

Clinical Cancer Research

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Purpose: We evaluated the expression of seven therapy-related genes to predict the clinical outcome of advanced gastric cancer patients treated with a neoadjuvant chemotherapeutic protocol. Experimental Design: Pretherapeutic, formalin-fixed, and paraffin-embedded biopsies of 61 patients, who received a 5-fluorouracil (5-FU)^and cisplatin-based chemotherapy were studied. The expressions of the 5-FU^related genes TS, DPD, and TP and of the cisplatin-related genes ERCC1, ERCC4, KU80, and GADD45A were analyzed by quantitative real-time PCR.The expression levels of single genes and of various combinations were tested for an association with response and overall survival. Results: High DPD levels were more frequently found in nonresponding patients and were associated with worse survival. GADD45A and TP levels showed weak associations with response, but GADD45A expression correlated with survival. There was no association with response for TS expression, but tumors with a high TS level were associated with worse survival. The combination of GADD45A and TP revealed the strongest predictive effect. High expression values of TP and/or GADD45A were exclusively found in nonresponding patients (P = 0.002) and were associated with a significantly poorer survival (P = 0.04). Conclusions: Combined gene expression levels ofTP and GADD45A represent a new variable to predict the clinical outcome after neoadjuvant chemotherapy in gastric cancer. The association of DPD expression with response and survival underlines a predominant role of DPD to predict 5-FU sensitivity.The association ofTS expression levels with survival but not with response suggests an importance of this gene for tumor progression.

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“…21,22 Our preliminary data suggested that the recommended dose of 5-FU was 20 mg/kg per body. Tumor growth inhibition studies have been done in vivo with 5, 7.5, 10, and 20 mg/kg of S-1.…”

Section: Myelosuppression and Gastrointestinal Injurymentioning

confidence: 99%

Comparison of alternate-day versus consecutive-day treatment with S-1: assessment of tumor growth inhibition and toxicity reduction in gastric cancer cell lines in vitro and in vivo

et al. 2008

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Prediction of sensitivity to fluoropyrimidines by metabolic and target enzyme activities in gastric cancer

Cited by 33 publications

References 39 publications

Unexpected Side Effects of a High S-1 Dose: Subanalysis of a Phase III Trial Comparing Gemcitabine, S-1 and Combinatorial Treatments for Advanced Pancreatic Cancer

Unexpected Side Effects of a High S-1 Dose: Subanalysis of a Phase III Trial Comparing Gemcitabine, S-1 and Combinatorial Treatments for Advanced Pancreatic Cancer

Combined GADD45A and Thymidine Phosphorylase Expression Levels Predict Response and Survival of Neoadjuvant-Treated Gastric Cancer Patients

Comparison of alternate-day versus consecutive-day treatment with S-1: assessment of tumor growth inhibition and toxicity reduction in gastric cancer cell lines in vitro and in vivo

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